The term "iodine deficiency disorders" (IDD) has
recently gained some currency as a designation for those
disorders which arise in man because of a deficiency of iodine in
the diet (1). The term has value because it encourages
speculation and experiment. For example, does a uniquely
definable syndrome of endemic proportions, such as deafmutism, in
a community where goitre, the established result of chronic
iodine deficiency, is endemic, have a causal relationship to
iodine deficiency?

When the mean daily intake of iodine in a community is less
than about 25 mg per day, many adults
have sizeable goitres and substantial numbers of people have
physical characteristics, including profound mental retardation,
that have been recognized as being associated with a high
prevalence of goitre. Individuals affected thus are called
endemic cretins. When the mean daily intake of iodine is above 25
but less than 60 mg per day, goitre may also be found in some
adults and in many children, but those conforming to the clinical
patterns of classic cretinism will not be found, excepting
occasionally older ones from an earlier time when conditions were
different. Other disorders may be associated with endemic goitre
but are less clearly the result of iodine deficiency. Among these
are endemic mental and statural retardation, endemic neuro-motor
deficiency, and endemic deaf-mutism. The origins of these
disorders are difficult to identify with certainty because of
complicating poverty, poor nutrition, regional genetic
differences, social and educational deprivation, climate, and so
on.

IDD is not a trivial problem. A quarter of the world's
population subsists on a diet that is deficient in iodine, i.e.
Iess than 60 g per day (2), and are at risk for I DD. Vast
regions of the less well developed countries harbour large
numbers of people with obvious goitre and many who show the
stigmata of cretinism. IDD continues to be a major public health
problem in spite of the availability of simple means of
prevention, but its impact on social development remains to be
fully assessed.

GEOGRAPHICAL DISTRIBUTION

Endemic goitre is found almost wherever it is looked for in
the developing countries, and it exists in localized regions in
some of the economically advanced countries of the West (3, 4).
The entire Andean chain is a major endemic region. Where iodide
prophylaxis has not been introduced, large nodular glands may be
seen in many adults (fig. 1), and among school children distinct
enlargements of the thyroids conforming to WHO grade-1 goitre may
appear in 30 or more per cent.

Cretinism must be searched out. In a monogrph published 25
years ago by the World Health Organization, Clements wrote that
cretinism does not occur in the Andes (5). This error is
important, because it illustrates the unreliability of hearsay
evidence, and also because cretins are often sequestered from
view and may not be encountered in hasty surveys. Endemic cretins
are in fact quite frequently encountered in the Andes, as well as
to the east of the Andes in Peru, Ecuador, Colombia, Venezuela,
and Brazil (fig. 2).

A severe endemia stretches across equatorial Africa. IDD is
found all the way from central Nigeria, across the Cameroon,
through the Central African Republic and northern Zaire, over to
the border of Uganda and Rwanda. It is also found in the Sudan
and is reported farther south in Tanzania and Zimbabwe (6). There
is an endemic area in Algeria, especially to the east in the
Kabile region. In northern Zaire there are communities where most
of the women are goitrous, and the prevalence of cretinism may
reach 10 per cent of the population.

Goitre is still found in southern Germany, Austria, and
Portugal (fig. 3). It is also well reported from Greece (7, 8)
and is found in the Middle East. A huge belt of severe IDD
stretches along the entire length of the Himalayan chain. One of
the most severe areas is the Terai of north India, where 140,000
persons are at risk (9, 10). The disease is also found reaching
eastward into Burma, Vietnam, Thailand, and New Guinea. The
People's Republic of China has been surveyed and large pockets of
severe disease have been mapped (11, 12). The disease is
doubtless present in parts of the Soviet Union, but little
epidemiological information is available.

SIGNIFICANCE OF ENDEMIC GOITRE

Endemic goitre in and of itself is probably not a particularly
significant disorder. If the gland becomes enlarged to the point
that it interferes with normal physical activity, or is
cosmetically unacceptable, or if it causes undue pressure on the
trachea or interferes with swallowing, then treatment is needed,
and prevention would have been desirable. Usually the enlarged
gland is functionally competent for the physiological needs of
the subject. When the endemia is severe, hormone production may
be com- promised. Evidence for an increased risk for neoplastic
degeneration in these glands is scanty (13).

The significance of IDD lies primarily in its impact on growth
and intellectual development. When iodine deficiency is most
severe, neonatal hypothyroidism occurs (14), and cretins are
found in the community. These individuals impose a burden on
community resources and on family life. What may be much more
important is the possibility that there are a large number of
people who do not have any of the classic features of cretinism
but whose linear growth, intellectual attainments, and
neurological functions are compromised by iodine deficiency. If,
as postulated, these people in fact exist - and there is
accumulating evidence that they do - then the central
significance of endemic goitre lies with them. The evidence for
their existence will be examined below.

PATTERNS OF CRETINISM

Sir Robert McCarrison, working in northern India in the first
decade of this century, first differentiated cretinism into two
types, a myxoedematous form and a neurological form (15).
Subsequent study has blurred but not eliminated the distinction,
and McCarrison noted that between the two there were overlapping
signs and that subjects with mixed forms were often found. The
typical neurological cretin has profound mental deficiency, a
characteristic facies, a shuffling gait or inability to walk at
all, a spastic diplegia which tends to affect the proximal more
than the distal extremities, other spastic signs, sometimes
squint, shortened stature, and usually, but not always, a nodular
goitre (16). In some the thyroid may be replaced by a fibrous
remnant. The subject is usually, but not always, deaf and mute,
or if not, usually has diminished auditory acuity in the higher
frequencies and also some degree of dysarthria. Hypothyroidism
may or may not be present.

The typical myxoedematous cretin, as described most vividly by
the group of investigators from Brussels working in Zaire
(17-19), is different. Mental deficiency is severe, and linear
growth is much more attenuated than in the typical neurological
cretin. Bone age may be astonishingly delayed. Hearing is usually
present. Such an individual is myxoedematous, both clinically and
by rigorous laboratory testing. The thyroid gland is typically
not prominent, and radioactive iodine uptake values are somewhat
less than those of their peers, but turnover is accelerated.
Neurological signs are much less prominent. Cretins with these
physical findings comprise about 90 per cent of those seen in
Zaire but a much smaller percentage elsewhere (fig. 4). In all
endemias subjects showing features of both types are found,
although the proportions vary widely from one endemia to the
next.

Recently, the neurologist DeLong has had an opportunity to
examine nearly a hundred cretins from the endemias of Ecuador and
Zaire (20 and personal communication). He points out that the
neurological findings are, indeed, much more common among the
Andean group and that signs of hypothyroidism are much more
common among those from Zaire. He noted that the spasticity tends
to be proximal, with relatively good preservation of distal motor
function and attributes this to damage to the rubrospinal tract.
He noted the preservation of many important functions, such as
vision, taste, sleep patterns, thirst and hunger, body
temperature control, and in most, conjugate movements of the
eyes. DeLong makes the point that the myxoedematous cretins of
Zaire conform much more to the clinical appearance of
congenitally hypothyroid children from non-endemic regions that
are untreated than do the neurological cretins.

What might be the reasons for the striking differences in the
clinical manifestations of endemic cretinism in different
endemias and among different subjects in the same endemia? It is
possible that toxic substances in the diet may play a role The
thyroid of the Zaire cretin is clearly damaged because it fails
to grow in spite of astronomically high plasma levels of
thyrotropic hormone (21). No specimen of such a thyroid has
become available for examination. In this regard it is
interesting that the Indians of southern Venezuela are deficient
in iodine but do not have goitre (22). Other factors may
contribute to the differences.

Differential death rates could play a role (23). Thus,
possibly the African cretins born with neurological damage may
fail to survive because of the rigours of the environment or the
level of maternal care. Those less affected may survive, and, if
iodine deficiency continues, they fail to develop; or if the
supply of iodine improves, they may grow and appear in the
community only as retarded persons.

One can only be astonished at the care given to the severely
damaged cretins of the Andean region, as evidenced by the
survival of the most extraordinarily retarded and deformed
individuals, who require the total care of their parents. Without
such care surivival would be impossible, and perhaps this kind of
parenting is not provided in central Africa. Now that screening
programmes for neonatal hypothyroidism are in progress in both
regions, it will be possible to know whether there are indeed
differential survival rates between the two regions. The
mortality rate is high among neonatally hypothyroid infants in
the central African setting (24).

Much study has been directed to a possible role of cassava in
endemic goitre and cretinism (25, 26). Poorly prepared cassava
yields an abundance of cyanide, which is converted to thiocyanate
after ingestion, and thiocyanate competes with iodide for entry
into the thyroid. A reciprocal relationship has been found in
Zaire between thiocyanate in the urine and iodine in the urine,
with respect to goitre (27), but no such correlation was found in
a recent study in Thailand (28). At present there appears to be
no convincing evidence that cassava is the determinant of the
clinical differences between the two types of cretinism, but only
that it may accentuate an existing iodine deficiency.

A number of observers have been struck by the frequency with
which people in moderately severe to severe endemias have minor
neurological deficits, but seem otherwise normal and function at
a useful level in their relatively undemanding communities (fig.
5). This has led to the speculation that overt cretinism is but
the tip of an iceberg of damage from iodine deficiency. Attempts
to test this hypothesis have been numerous and almost invariably
flawed. It is exceedingly difficult to test intellectual capacity
and performance across language and cultural barriers and to
extricate the role of iodine deficiency from the many other
factors - dietary, social, educational, environmental, and
cultural - that may contribute to such differences as may be
observed.

Fierro-Benitez et al. and Dodge et al. found evidence that
administration of iodized oil prior to the first trimester of
pregnancy improved test performance in the progeny at a later
date (29-31). Similar results have been obtained in Bolivia (32)
and in Papua New Guinea (33). Bleichrodt et al. carried out
intensive studies in central Java and found that administration
of iodine improved the results of tests of fine motor control,
but changes in intellectual function were not convincing (34,
35). Their study was marred by differences in educational
attainments between the villages that were tested. Thilly et al.
have concordant data from Zaire (36).

Recently Fierro-Benitez in Ecuador has examined the
performance of children born of mothers who were given iodized
oil prophylactically before or soon after conception. He found
that the children who finished at least one year of school and
were born of mothers who were injected before the second
trimester of pregnancy performed better in terms of scholastic
achievement and school drop-out rates and in tests of performance
that measured neuromotor function but not intellectual
performance (37).

None of these studies is entirely convincing by itself, but
the accumulated information points in the direction of an effect
of iodine administration in improving performance when given
before conception, and perhaps even when given during the early
post-natal years. Indeed, it is my firm opinion and that of
others that the data are sufficiently convincing to strongly
support major efforts at iodine prophylaxis wherever endemic
goitre of more than minimal prevalence is found. Further, the
finding of endemic cretinism, if more than a historic relic of a
time before adequate prophylaxis was introduced, constitutes the
strongest demand for a crash programme of prophylaxis.

A shocking example of failure to implement a prophylactic
programme is the Indian Terai, where the Gangetic plain is
populated by a huge number of people at risk for iodine
deficiency disease, and by untold thousands who have already
suffered irreversible damage (38, 39). Thousands of infants in
this region are born every day with a risk of damage that can
only promote the continuation of the social and economic
backwardness of this region. Another example is Bhutan, where a
recent survey has revealed a high prevalence of iodine deficiency
disease (40).

AETIOLOGICAL FACTORS

There can be no question that iodine deficiency is the central
cause of endemic goitre in most, if not all, endemias. Goitre
does not entirely disappear from a community when iodine
prophylaxis is applied because there are other recognized
categories of thyroid enlargement that are not related to iodine
deficiency, but these will give only a 5 per cent or less
incidence of goitre in any region where the intake exceeds 100 mg of iodine daily. Among these are chronic
thyroiditis, Graves' disease, familial metabolic goitre, and
simple and adolescent goitre of unknown cause.

Do factors other than iodine deficiency play a contributing,
accentuating, or even primary role? Gaitan has noted that iodine
prophylaxis has not eliminated goitre from the endemic regions of
Colombia, but the programme trivialized the endemia (41). He has
identified certain sulphides that are antithyroid in action in
waters from certain wells (42). Water from certain rock
formations and not from others corresponds to goitre downstream
(43). He also has found evidence for goitrogens in contaminated
water from West Virginia where goitre occurs (as did McCarrison
in northern India many years ago, ref. 3), and has found
goitrogens in the effluent from certain chemical plants in the
south-central United States (44).

Virtually no evidence has been found for a genetic factor.
Goitrogenic activity has been detected in milk in Finland (45).
Bacterial and viral aetiologies have been suggested. Does the
newly described thyroid-growth-promoting immunoglobulin
contribute to endemic goitre (46)? An increased plasma titre has
been found in some patients with endemic goitre but not in others
(47). An increase has been found in the plasma of other patients
with thyroid growth from other causes, such as Graves' disease,
so that its presence may be non-specific, but the possibility
deserves thorough exploration because of certain anomalies that
have been described, such as the lack of goitre in
iodine-deficient Indians in southern Venezuela, and the lack of
goitre in the myxoedematous cretins of Zaire. The pathogenesis
and evolution of endemic goitre has been thoroughly investigated
by Studor and is reasonably well understood (48).

As with endemic goitre, so with endemic cretinism, iodine
deficiency appears to be the central, necessary, and sufficient
condition. Hetzel and his colleagues in Australia have developed
a sheep model for iodine deficiency (49, 50). Their ewes are fed
on a fodder collected from areas known to be depleted of iodine.
The progeny of these ewes are severely malformed, have
underdeveloped central nervous systems, large hyperplastic
goitres, and delayed intrauterine osseous development and do not
survive birth by more than a few hours. The newborn iambs appear
to be nearly normal if iodine is administered to the ewe at the
beginning of the third trimester of pregnancy, but neuromotor
performance of the matured animals has not yet been reported.

The argument is sometimes made that cretins are often
euthyroid (51). This might be expected if iodine becomes
available after the critical period when the damage is done. Many
of these cretins have functioning thyroids, and if given a supply
of iodine there is no reason why production of thyroid hormone
should not begin and permit a euthyroid state. There is nothing
anomalous about a euthyroid cretin, nor does the finding of such
a cretin constitute an argument against iodine deficiency as the
cause of the initial damage.

The vexing problem remains: why is there such breadth to the
clinical spectrum of endemic cretinism? Some possible answers are
suggested earlier and can be tested. While the question is
interesting and in need of pursuit, the fact is that cretinism
does not appear in newborns after iodine has been supplied to the
population at risk.

PREVENTION

Addition of iodide or iodate to table salt is the standard
method of preventing iodine deficiency disease. Cretinism
vanishes, and the prevalence of goitre almost invariably drops to
5 per cent or less if the iodine actually reaches the consumer.
The programmes in North America and most of the countries of
Europe have been highly successful. A programme with iodated salt
was most successful in the highly endemic region of Guatemala
until recently, when it has been permitted to lapse, and goitre
appears to be returning to that country.

Programmes of iodized salt have failed where the iodization
was not properly done or where hot and humid conditions caused
the disappearance of the iodide into the containers or the
atmosphere or most commonly where manufacture was sloppy or
neglected. Recently three containers of iodized salt were
purchased from a local merchant in the United States and sent to
Dr. H. Burgi in Switzerland for analysis. The labelled content of
iodine corresponded closely to the results of analyses. Thus, it
is possible to iodize salt and have it retain its concentration
for a long period of time under varying conditions. But the
iodine must be added in the correct amount, and the salt stored
and transported under proper conditions. Quite recently some
analyses of commercial iodized salt in a Latin American country
showed that the content was far below that specified on the
label.

It would seem that such an important disease which has such a
simple method of prevention would no longer exist. A number of
conditions account for failure. Thyroid disease to the casual
observer does not have the drama or startling impact of a disease
like smallpox or diphtheria. It fails to catch the eye of the
politician in the seat of government. It tends to be a rural
disease, and politicians often do not appear in the rural areas
where the disease exists. Goitre is found among people who often
have little if any voice in their governments. It may be taken
for granted and seen as a part of life or the normal state. Its
impact at the subtle level of a decline in intellectual
performance may not be recognized. The very existence of goitre
and cretinism may escape the interest of local health personnel.

One colleague visiting in the sub-Himalayan region was told by
the local physician that cretinism did not exist in his district,
but many cretins were found in the houses and back yards of the
poor living in shacks on the hills above the village. The medical
officer had never visited beyond the village. I recently spent a
day visiting villages and finding cretins with a journalist from
the capital city of a Latin American country He had never been in
a village in his own country and was astounded by what he saw.

Indifference or ignorance at the level of either responsible
governmental health personnel or ministries or governmental
inflexibility are probably the most important factors
contributing to the continuing existence of iodine deficiency
disease. India, with one of the largest populations at risk in
the world, has talked about iodization of salt for at least 25
years, and the proposed programmes are still entrapped in the
Laocoonian coils of the federal bureacracy. To a large degree
iodine deficiency disease is a social-political problem, rather
than a medical-biological one.

There are, of course, regions in the developing countries
where iodization of salt is not at present a solution because
there are no widely used commercial channels for the
merchandising of salt, or because the salt enters the country
through multiple ports so that iodization is not practical, or
because the salt comes from cottage industries or other local
sources and the scale is too small to make iodization
practicable. For such places iodized oil is an alternative.
iodized poppy-seed oil (or certain other vegetable oils which
have unsaturated double bonds) can be injected intramuscularly or
taken orally. The iodine is released very slowly. A single dose
of 2 ml may supply the iodine needs for the individual for two
years or more if given intramuscularly. Highly successful
programmes are in progress in several countries, including Zaire,
Ecuador, Peru, Papua New Guinea, and Indonesia. All evidence
points to the safety and effectiveness of these programmes.
Iodized oil is particularly useful when the lag time of a salt
iodization programme and the urgency of the situation are such
that an immediate interruption of the iodine deficiency state is
imperative. This is the nature of affairs in the Indian Terai at
the present moment iodized oil prophylactic programmes have
certain drawbacks. They require substantial logistical support.
Administration must be by sterile needle. Personnel must be
appropriately trained. Records must be kept. The rare occurrence
of post-injection thyrotoxicosis implies the need for occasional
medical monitoring (but not different from after iodized salt
administration). For a given time span of protection, iodized oil
is more expensive than iodized salt. In spite of these drawbacks.
iodized oil offers great hope to millions who otherwise may wait
for months or years before the risk of iodine deficiency disease
is no longer a threat to their children. The feasibility of
iodized oil by mouth is currently being explored.

Other forms of prophylaxis have been used. Bread has been
iodinated, and in Tasmania (52) this resulted in a small epidemic
of thyrotoxicosis. Recently a system has been devised for
introducing a casette containing iodine crystals into a bypass of
a city water supply in a town in Sicily where endemic goitre was
found (53). The cost on a per-capita-per-year basis was
acceptably low, and the technique was effective in reducing the
prevalence of childhood goitre. While this method may be
effective, in most parts of the world where endemic goitre is
found there are no public water systems that would lend
themselves to this form of supplementation.

SOME QUESTIONS IN NEED OF ANSWERS

1. What are the determinants of the differences between
myxoedematous and neurological cretinism? Are there dietary
components that damage the foetal thyroid in the myxoedematous
type, or does a differential death rate account for the
epidemiological differences? What is the outcome of neonatally
identified hypothyroid subjects in endemic areas with thyroid
hormone replacement therapy? Would iodized oil be adequate
treatment for such infants?

2. What are the audiometric findings in cretins of both types
who appear to be able to hear? What can be learned from evoked
auditory and ocular potentials in these patients?

3. How much catch-up growth can be gained in the young
myxoedematous cretin by hormonal or iodine treatment ?

4. What has been the death rate among neonatally identified
hypothyroid subjects in endemic regions?

5. What is the true rate of hyperthyroidism after
administration of iodized oil? Reports vary quite widely, but
there is no careful study with frequent follow-up. Is the
hyperthyroid state really transient, as has been claimed?

6. What is the incidence of hyperthyroidism after oral vs.
intramuscular administration? What are the relative retention
rates over several months following the two routes of
administration? What is the mode of transport of the iodine after
the two paths of administration? It is possible that the iodine
is transported by different mechanisms if it reaches the liver
first or is mobilized from a muscle depot.

7. Are there less expensive ways of dispensing iodized oil
than by commercial purchase and distribution by highly trained
personnel?

8. What if any is the role of thyroid-growth-stimulating
immunoglobulin in endemic goitre? Is this factor absent in the
myxoedematous cretins of Zaire and the goitre-free
iodine-deficient Indians of the Alto Orinoco? Does this substance
rise with production of goitre experimentally, as with a
goitrogen? Does it disappear with thyroidectomy; i.e., is its
source the thyroid itself?

9. Can a more convincing study be devised that will
unequivocally demonstrate whether prophylaxis with iodized salt
or oil improves neuromotor function, intellectual development, or
skeletal growth?

10. Do the goitrogens that have been identified in effluent
water from sedimentary rocks in Colombia, well water from
Colombia, and stream water from goitrous regions of Kentucky have
a real role in causing goitre? What is the chemical identity of
these substances? Can their blocking effect be overcome by
administration of iodine?

11. Does iodine have any role in foetal development before the
foetal thyroid begins to function? Is the placenta normal in
iodine deficiency? Do maternal thyroid hormones cross the
placenta and affect the foetus before the foetal thyroid starts
functioning? Will a metabolically active iodine-free thyroxine
analogue support normal foetal growth in the mother on a very low
iodine diet?

12. What is the real role of iodine and of the thyroid
hormones in the development of the ear? Is the structure of the
middle and inner ears of the cretin sheep model of Hetzel et al.
normal? Why do these animals not survive? Is it due to failure of
some key enzyme to mature, or is it because of pulmonary failure,
or does the circulatory shift that normally occurs at birth fail
to happen?

SUMMARY

Endemic goitre continues to be a major public health problem
in many of the developing countries. Probably a quarter of the
world's population is at risk. In many endemias, especially those
of India and central Africa, the disease and its accompanying
disorders are responsible for serious disability and contribute
to economic and social backwardness. While mild endemic goitre
constitutes no particular disadvantage, when moderately severe or
severe, the larger goitres may be a serious burden to the medical
care system, and the attendant cretinism and lesser degrees of
neuromuscular and intellectual impairment are surely important
iodine deficiency disease is readily preventable by measures that
are cost effective. Low viability of the disorder on the one hand
and governmental inattention on the other are responsible for
continued high prevalence rates. While there is ample information
to support immediate implementation of prophylactic programmes in
regions of endemic iodine deficiency disease, there remain
interesting questions for research, the answers to some of which
at least might affect the design and execution of prophylactic
programmes and would certainly advance our understanding of
iodine deficiency disease.

27. P. Courtois, P. Segghers, M. Mafuta, and P. Delange,
"Role of the Balance between the Dietary Supplies of iodine
and Thiocyanate in the Etiology of Endemic Goiter," paper
presented at the 11th meeting of the European Thyroid
Association, no. 58, 1981.

30. Trowbridge, F.L., "Intellectual Assessment in
Primitive Societies, with a Preliminary Report of a Study of the
Effects of Early Iodine Supplementation on Intelligence,"
J.B. Stanbury and R.L. Kroc, eds., Human Development and the
Thyroid Gland (Plenum, New York, 1972), p. 137.